alpha-amino-beta-hydroxycarboxylic acid amides



pounds are then reduced.

3,101,367 oc-AMlN-B-HYDR@XYUXYLIC ACID AMEDES Gustav Elli-hart, Bad Sodcn, Taunus, Ingeborg Hcnnig,

Kelkheim, Taunus, Karl Schmitt and Ernst Lindner,

Frankfurt am Main, and Heinrich Ott, Eppstein, Taunus, Germany, assignors to Farhwerke Hoechst Aktiengesellschaft vormals Meister Lucius & Eriining, Frankfurt am Main, Germany, a corporation of Germany No Drawing. Filed Aug. 4, 1959, Ser- No. 831,488 Claims priority, application Germany Aug. 16, 1958 6 Claims. (Cl. 260-561) German patent specification 963,776 describe-s oc-fiHliIlO- fi-hydroxybutyric acid anilides which have good antiphlogistic properties. 3

The present invention relates to novel a-amino-fi-hydroxycarboxylic acid amides of the general formula wherein R represents an aliphatic hydrocarbon radical containing a tertiary carbon atom bound to the nitrogen atom, are treated with nitrous acid or said acetoacetic acid amides are substituted in the DL-PUSitlOH by an aryl-a zo group, and the nitroso or the aryl-azo group and the keto group in the nitrosat-ion products or in the aryl-azocomnitroso group, carried out by the treatment with nitrou acid, is hereinafter referred to as nitrosation.

According to one possibility of carrying out the process of the. present invention, the acetoaceticacid amides of the above-indicated formula are treated with nitrous acid and the nitrosation products then reduced. The acetoacetic acid amides used as starting substances can be prepared in known manner, for example, by reactingsui-table amines with diketene. As such starting substances, there may be used, for example, acetoacetic acid-tern, butyl amide, acetoacetic tacid-2-methyl-butyl- (2)-amide, acetoacetic acid 3-methyl-pentyl-(3)-amide, acetoacetic acid-3- ethyl-pentyl-(3)-amide.

For carrying out the nitrosationof the carbon atom in u-position it is preferred to dissolve the ,B-ketocarboxylic acid amide in glacial acetic acid and then to nitrostate by addition of a concentrated aqeuous solution of sodium nitrate. The S-ketocarboxylic acid amide may also be dissolved in an organic solvent and then nitrosated by adding sodium nitrite and mineral acids. As organic solvents, there may be used, for example, low molecular weight aliphatic alcohols. As mineral acids, sulfuric acid or hydrochloric acid are preferably used. I

An advantageous possibility of further reacting the'is'o nitroso compounds, obtained as intermediate products, to the desired u-amino-fl-hydroxycarboxylic acid amides is represented by the following working method by which good yields areattained: At first, the isonitroso compounds (The introduction of the isoare treated with reducing agents in a manner allowing only the isonitroso group to be converted into the amino group. As reducing agents there may be used in this case, for example, nascent hydrogen obtainable by the action of dilute acids on, for example, base metals such as zinc, iron or tinsodium hydrosulfite or tin (II) chloride. In

' the thus obtained a-amino-fi-keto compounds, the reduction of the keto group to a secondary alcohol group is then effected in a separate reaction.

However, it may be of advantage, to intermediarily protect the amino group in a-position by acylation. As acylating agents, there are suitable acid derivatives, for example, acid halides or acid \anhydrides such as acetyl chloride, propionyl-chloride, benzoyl chloride, phenylacetic'acid chloride, or the corresponding acid anhydride. If this working method is used, it is not necessary to isolate the intermed-iately forming a-amino compounds; the acylating agent can be added immediately after termiantion of the reduction of the isonitroso group. If, however, nas

cent hydrogen is used whichwas recovered by treating I base metals with acids, it may be suitable to neutralize the solution by means of sodium acetate before adding the acylating agent The same a-acylarninoacetoacetic acid amides can also be prepared via the a-aryl-azo acetic acid amides.

According to another possibility Within the scope of the process of the present invention, the acetoacetic acid amides used as starting substances are suitably converted into the a-aryl-azo compounds by reacting them with an aryl-diazonium salt. The aryl-diazo'nium salt solution required for the reaction can be prepared, for example, from an aromatic amine, such as aniline, with the aid of sodiumnitrite. The solution so obtained is then introduced dropwise into a solution of the ketocarboxylic acid amide used as starting substance, which it is preferred to neutralize, for example, with sodium acetate. As solvent, it is suitable to use a mixture of water and low molecular weight aliphatic alcohols. The m-aryl-azo' compound addition or shortly after termination of the addition; after completed precipitation it can be recovered from the solution by filtration with suction with almost quantitative yield and in so pure a state that in most cases it can be further processed in the manner described below.

Another possibility within the scope of the process of the present invention for converting the oc-BIYl-QZO-B-KGIDO- carboxylic acid amides obtained as intermediate product into the desired a-amino-fl-hydroxycarboxylic acid amides corresponds to the already described workingmethod for the further processing of the nitrosation products, which may likewise be carried outwith good yields. The keto-group in the a-amino-fi-keto compounds obtained is subsequently reduced in the manner described above for the nitrosation products to a secondary alcohol group in a separate reaction; also in this case it is suitable to intermediarily protect the amino group in a-positionby acylation, and it is likewise in this case not necessary to isolate the intermediately formed a-amino compounds. If the reduction is not carried out in the presenceof the acylating agent, the latter can also be added directly after the reduction of the a-aryl-azo group. If, however, nascent hydrogen recovered by treating base metals with acids is used, it may be suitable to neutralize the solution by means of sodium acetate before adding the acyl-ating agent The aromatic amine likewise produced in. this cleavage reaction is, as expected, likewise acylated under these reaction conditions. This acylation product, however, is in general easier soluble than the desired product and can thus be removed fromthe latter byfractional distillation. I

The reduction of the keto group in the a-acylamino 1?, acetoacetic acid amides obtained according to the two working methods described hereinbefore can be realized, for example, by means of sodium or aluminum amalgame in the presence of alcohols. It is also possible to use sodium boron hydrided, or to operate with electrolysis. Oatalytical hydrogenation using, for example, such catalysts as belong to the 8th group of the periodic system, preferably nickel catalysts, can be carried out with particular results; Raney catalysts may also be used with advantage. As solvent, there can be used organic solvents, preferably low molecular weight aliphatic alcohols, if necessary in the presence of water. The operation is suitably conducted at room temperature or at slightly elevated temperatures, preferably in the range of 50 and 80 C.

The separation of the acyle group from the u acylamino-fl-hydroxycarboxylic acid amides thus obtained can be carried out according to conventional methods, for example, by saponification with mineral acids, preferably with hydnohalic acids, more particularly with hydrochloric acid or hydrobromicacid.

It is also possible so to vary the Working method of the process of the present invention leading via the nitrosation products that the operation is carried out without isolation of the a-isonitroso-acetoacetic acid amides. Also in this case the starting substances are nitrosated, as described above, with sodium nitrite in the presence of acids, but the resulting reaction mixture is then directly reduced. By adding the acylating agent after terminated reduction there is obtained in this case directly the corresponding a-acylamino-acetoacetic acid amide. The same variation may also be applied in the preparation of the arylazo compounds, the isolation of which may also be dispensed with by directly reducing the reaction mixture and by then immediately adding the acylating agent. The reduction of the keto group in the a-arninoor wacylaminoacetoacetic acid amides, to the corresponding a-aminoor a-acylamino-fi-hydroxybutyric acid amides, is subsequently carried out in the manner described above.

A particularly advantageous method of preparing the products of the present invention consists in the simul taneous reduction in one operation of the isonitroso or the arylazo group in u-position and the keto group. This reduction may be effected, for example, with the aid of catalysts, for example, metals of the 8th group of the periodic system, preferably with nickel catalysts. There may also be used, for example, noble metalsor Raney catalysts. As solvents, there may be used organic solvents, preferably low molecular weight aliphatic alcohols, if necessary in the presence of water. The :operation is suitably conducted at room temperature or at slightly elevated temperatures, preferably in the range of 50 and 80 C. It is also possible to effect the reduction by means of nascent hydrogen obtained, for example, from sodium or aluminum amalgame and alcohol, or with sodium boron hydride. The reduction may also be carried out electrolytically. After removing the catalyst, there is obtained directly the desired a-aminoaB-hydroxycarboxylic acid amide.

When operating on an industrial scale, there are obtained particularly good yields and very pure products by hydrogenating either by discontinuously injecting a solution of a-isonitroso-acetoacetic acid amides, obtained as intermediate products by nitrosation of the acetoacetic acid amides, at a pressure of 50 to 100 kg/cm. and, if necessary, at an elevated temperature, to a suspension of the catalyst, or by pumping a solution of the oc-iSOIIitI'OSO- fl-keto-carboxylic acid amides at a pressure of 50 to 100 kg./cm. and, if necessary, at an elevated temperature, through a continuously operating hydrogenation apparatus, the catalyst being either suspended in this solution or contained in the apparatus in granulated form. The particular advantage ofiered by the last mentioned working method [of the process of the present invention, which includes the simultaneous reduction in one single operation step, consists in the possibility of conducting the operation in such a manner that the isonitroso group as well as the keto group are reduced as simultaneously as possible. The same is true of the simultaneous reduction of the a-arylazo group and the p-keto group, realized in one operation. It has been found that there may ocour side reactions as have already been described in the literature (cf. for example, I. Am. Chem. Soc., 60, page 1328 (1938)) consisting in the condensation of 2 moles of a-amino-fl-keto-carboxylic acid derivatives to the corresponding heterocyclic compounds By the reaction with inorganic or organic acids, the compounds so obtained may be converted into the corresponding salts. As inorganic acids, there enter into consideration, for example, hydrohalic acids such as bydrochloric acid and hydrobromic acid, phosphoric acid and arnidosulfonic acid. As organic acids, there may be mentioned by way of example; formic acid, acetic acid, oxalic acid, malonic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, hydroxyethane sulfonic acid, aceturic acid, phenyldimethylpyrazolonemethyla aminomethanesulfonic acid, ethylenediamirre-tetracetic acid, benzoic acid and salicylic acid, and the derivatives thereof. These are physiologically compatible acids.

The products obtained by the process of the present invention are valuable medicaments which have a very good analgesic action while showing a relatively low toxicity. Thus, 100 mg. per kilogram of ot-amino-B-hydroxy-butyric acid-3-ethyl-pentyl-(3)-amide hydrochloride, subcutaneously applied, produced in mice a distinct analgesic effect. The reaction time was prolonged from an average period of 7.7 seconds to an average period of 23.9 seconds. As regards their analgesic properties, the products of the present invention are superior, to the known compounds of not only comparable but also of different chemical configuration, as is proved by the following: A dose of 1 gram/kilogram of fi-hydroxybutyric acid-pphenetidide (cf. German patent specification 964,057) orally applied produced a prolongation of the reaction time from 5 seconds to 19.8 seconds only (average value in- 20 mice); an increased dose of 1.5 .g./kg. of the same compound caused prolongation of the reaction time from 5.7 seconds to 25.9 seconds (average value in 30 mice). In addition to the higher efficacy, the products of the present invention are distinguished over the known products by the great advantage that they are water-soluble, thus allowing their application by subcutaneous injections,

whereas the known products can be applied per os only.

When comparatively testing the sodium phenyldirnethylpynazolonemethylaminomethanesulfonate it was found that 1 gram/kilogram of this known analgesic has, subcutaneously applied, about the same efficaoy as 100' mg./

' kg. of aamino-B-hydrQXybutyric acid-3-ethylphentyl-(3)- amide-hydrochloride. The toxicity of the latter product, when administered intravenously, amounts to 100 mg./ kg. (dos. let. min.). Clinical tests conducted for orientati'on showed that the a-amino-fi-hydroxybutyric acid ethyl-pentyl-(3)-amide, when administered per es in the form of its free base or as hydrochloride in a single dose of 300 to 500 mg. produced the expected analgesia. These tests were carried out in patients sufiering from various pains (toothache, neuritis, sciatica, headache, postoperative pains, tumor pains, and the like).

The u-amino-p-hydroxybutyric acid anilides, mentioned in the first paragarph of this specification are known compounds, practically do not display any analgesic action. It, therefore, has been the more surprising that the products of the present invention possess such an excellent analgesic eflicacy. The following examples serve to illustrate the invention but they are not intended to limit it thereto;

EXAMPLE 1 a-Amino -fl-Hydroxybutyric Acid-Tert. Bmylamide (a) grams of acetoacetic acid-tert. butyl amide ob-' tained by the reaction of tert. butyl amine and diketene in benzene, are dissolved in 240 cc. of glacial acetic acid; to this solution is then added dropwise a concentrated aqueous solution of 40 grams of sodium nitrite. The reaction temperature is maintained at 20-30 C. After having concentrated under reduced pressure, a small amount of water is added to the residue and the latter is then extracted with ether. After drying and separation of the ether by distillation, there are obtained 93 grams of u-isonitrosoaacetoacetic acid-tert. butyl amide in crystalline form.

(b) A solution of 50 grams ofthis isonitroso compound in 1 liter of methanol is hydrogenated in a pressure vessel at a temperature of 95 C. in the present of a nickel catalyst deposited on kieselguhr. After the compound has taken up the calculated amount of hydrogen, which operation is completed within a short period, the whole is filtered and the filtrate is concentrated under reduced pressure. To the residue then is added 2 N-hydrochloric acid until it shows an acid reaction to Congo paper. After filtration with charcoal, the whole is rendered alkaline by means of a 2 N-sodium hydroxide solution and then extracted with ether. The syrupy ether residue is then converted by means of alcoholic hydrochloric acid into the crystalline hydrochloride of the a-amino-fl-hydroXy-butyric acid-tert. butyl amide having a melting point of 22l-222 C. (after recrystallization from alcohol).

EXAMPLE 2 a-Aminmfl-Hydroxybmyric Acid-Tert. Butyl Amide There are prepared two solutions:

Solution 1: 25 grams of aniline are dissolved in 88 cc. of concentrated hydrochloric acid and 265 cc. of water; to this solution is then added dropwise at 0 C. a solution of 18.8 grams of sodium nitrite in 55 cc. of water.

Solution II: A solution of 120 grams of sodium acetate in 200 cc. of water is combined with a solution of 42.5 grams of acetic acid-tert. butyl amide in 1.2 liters of alcohol.

Solution I is added dropwise to solution II while cooling and stirring.

Stirring is continued for one hour, the yellow precipitate that has formed is filtered off with suction and yields after recrystallization from alcohol 66 grams of a-phenylazo-acetoacetic acid-tert. butyl amide.

(b) 66 grams of a-phenylazo-acetoacetic acid-tort.

butyl amide are hydrogenated at 100 C. in 1 liter of methanol in the presence of Raney nickel as catalyst. After filtration and concentration of the filtrate, the latter is repeatedly mixed with water and concentrated in order so to remove the aniline formed by a side reaction.

After addition of 2 N hydrochloric acid until acid reaction to Oongo-paper, the residue is filtrated with charcoal and concentrated under reduced pressure. There are obtained 35 grams of a-amino-B-hydroxybutyric acid-tert. butyl amide-hydrochloride having a melting point of 222 C. (after recrystallization from alcohol).

EXAMPLE 3 a-Amino-fi-Hydroxybutyric Acid-Z-Methyl-Bulyl- (2) -Am ide In accordance with the working method described in Example In, 30 grams of acetoacetic acid-Z-methyl-butyl- (2)-amide are converted into the isonitroso compound. After hydrogenation in the manner dmcribed in Example 1b, there is obtained the a-amino-B-hydroxy-butyric acid- In accordance with the working method described in Example In, there are obtained from 100 grams of acetoacetic acid-B-ethyl-pentyl-(B)-amide 110 grams of the isonitroso compound. After hydrogenation in the manner described in Example 1b, there is obtained the a-amino-fihydroxy-butynic iacid-3-ethyl-pentyl-(3)-amide. By conversion into the hydrochloride in the manner described above, there are obtained the hydrochlorides of the a-amino-fl+hydroXy-butyric acid-3-ethyl-pentyl-( 3 -amide in their two isomeric forms (three and erythro form, respectively), which can be separated by fractional crystallization from alcohol. The high-melting compound melts at 222-223 C., the low-melting compound at 179- 180 C. The analytical values of both compounds are equal, only the ultra-red spectra are difierent.

EXAMPLE 5 a-Amino-fl Hydroxybutyric Acid-Terr. Butyl Amide To 50 grams of the u-isonitrosoacetoaceticacid-tort; butyl amide prepared according to Example 1a, therev are added 150 cc. of glacial acetic acidv and 50 cc. of acetic anhydride; into the reaction mixture, there are introduced, in portions and while stirring, 50 grams of zinc dust. After stirring for one hour at 40 C., 750 cc. of water are slowly added, while stirring is continued. After having stirred for several hours, the whole is filtered with suction and the filtrate is extracted with methylene chloride. After drying and separation of the solvent'by distillation, the residue crystallizes out. The melting point of the a-acetylamino-acetoacetic acid-tert. butyl amide thus formed is at 128130 C. (after recrystallization from ethyl acetate) 30 grams of the compound thus obtained are reduced in 100 cc. of methanol and 10 cc. of water with sodium boron hydride. After neutralization with dilute hydrochloric acid and extraction with methylene chloride, there are obtained 25 grams of u-acetamino-B-hydroxybutyric acid-tort. butyl amide having a melting point of 160162 C. (from acetic ester). j

20 grams of this compound are heated on the steam bath, with 20 cc. of concentrated hydrochloric acid and 20 cc. of water, for 20 minutes. After having been allowed to cool, the reaction mixture is rendered alkaline by means of dilute sodium hydroxide solution and shaken out with methylene chloride. After drying the separation hydrochloric acid.

EXAMPLE 6 The Phenyldimethylpyrazolonemethylaminomethanesulfonate of u-Amino-B-Hydroxybutyric Acid-3-Ethylpenty-l- (3)-Amide 10.8 grams of a-amino-B-hydroxybutyric acid-3-ethylpentyl-(3)-a mide and 15.55 grams of phenyldimethyl pyrazolonemethylaminomethanesulfonic acid are dissolved in 40 cc. of alcohol and filtered. After concentration under reduced pressure, there are obtained 26 grams of the phenyldimethylpyrazolone methylaminomethanesulfonate of oa-amino-fl-hydroxybutyric"acid-3-ethyl-pentyl-(3)- amide in the form of a white hygroscopic powder.

EXAMPLE 7 The Maleate of oc-Amino-fi-Hydroxybutyric Acid-3-Ethylpentyl-(3)-Am ide 18.1 grams of m-amino-flhydrOXybutyric acid-3-ethylpentyl-(3)-amide and 9.7 grams of maleic acid are dissolved in water. The residue is concentrated under reduced pressure and then dissolved in hot alcohol. After cooling, there [is formed a crystal mass. There are ob tained 25.5 grams of the maleate of a-amino-B-hydroxybutyric acid-3-ethy1-pentyl-(3)-amide. The compound melts at 132-133 C.

7 EXAMPLE 8 The Salicylate of a-Amino-B-Hydroxybutyric Acid-3- Ethylpentyl-(3)-Amide 17 grams of a-arnino-u-hydroxybutyric acid-3-ethylpentyl-(3)-amicle and 10.9 grams of salicylic acid are dissolved at about 40 C. in a small amount of alcohol. The solution is'mixed with water until turbid and with ice to yield a crystal mass. There are obtained 20.5 grams of the Salicylate of oc-amino-B-hydroxybutyric adid-3-ethylpentyl-(3)-amide; the compound melts at 148-149" C.

EXAMPLE 9 The 2,5-Dihydrxybenz0ate of cc-Amino-fi-Hyaroxybutyric Acid-3-EthyIpentyl-(3)-Amide wherein R represents an alkyl radical containing from four to seven carbon atoms and containing a tertiary'carbon atom linked to the nitrogen atom, and addition salts of such compounds with physiologically compatible acids. 2. a-Amino-fi-hydroxybutyric acid-tert. butyl amide.

3. a-Amino-fi-hydroxybutyric acid-Z-methyl-butyl-(2)- amide.

4. 0c Amino-fi-hydroxybutyric acid-3-ethylpentyl-(3)- amide.

5. 2,5-di hydroxybenzoate of ot-amino-fl-hydroxybutyric acAid-3-ethylpentyl- 3 -amide.

6. Salicylate of a-amino-fi-hydroxybutyric acid-3-ethylpentyl-(3)-amide.

References Cited in the file of this patent UNITED STATES PATENTS 2,017,537 Hofimann et a1 Oct. 15, 1935 2,446,651 HaItung Aug. 10, 1948 2,548,863 Bruce et a1. Apr. 17, 1951 2,601,387 Gresham et al June 24, 1952 2,851,494 Ehrhart et a1 Sept. 9, 1958 FOREIGN PATENTS 801,454 Germany Jan. 8, 1951 5th Series, vol. 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF ALPHA-AMINO-BETA-HYDROXY-CARBOXYLIC ACID AMIDES OF THE FORMULA 